ANTIDEPRESSANTS

An antidepressant is a psychiatric medication
or other substance (nutrient or herb) used for alleviating depression
or dysthymia ('milder' depression). Drug groups known as MAOIs,
tricyclics and SSRIs are particularly associated with the term.
These medications are now amongst the drugs most commonly prescribed
by psychiatrists and general practitioners, and their effectiveness
and adverse effects are the subject of many studies and competing
claims. Nutrients for which there are claims of antidepressant activity
include phenylalanine, tyrosine, tryptophan, 5-Hydroxytryptophan,
and choline.

Most antidepressants have a delayed onset of action and are usually
taken over the course of weeks, months or years. They are generally
considered distinct from stimulants, and drugs used for an immediate
euphoric effect only are not generally considered antidepressants.
Despite the name, antidepressants are often used in the treatment
of other conditions, including anxiety disorders, bipolar disorder,
obsessive compulsive disorder, eating disorders and chronic pain.
Some have also become known as lifestyle drugs or "mood brighteners".
Other medications not known as antidepressants, including antipsychotics
in low doses[1] and benzodiazepines,[2] are also widely used to
manage depression.

The term antidepressant is sometimes applied to
any therapy (e.g. psychotherapy, electro-convulsive therapy, acupuncture)
or process (e.g. sleep disruption, increased light levels, regular
exercise) found to improve clinically depressed mood. An inert placebo
tends to have a significant antidepressant effect, so establishing
something as an antidepressant in a clinical trial involves demonstrating
a significant additional effect.

History

Saint John's Wort

Opium[3] and St John's Wort[4] (as a "nerve
tonic") had long been used to alleviate depression, but the
contemporary history of antidepressant medications begins with isoniazid.

Isoniazid and iproniazid

In 1951, two physicians from the Sea View Hospital
on Staten Island, Irving Selikoff and Edward Robitzek, began clinical
trials to evaluate two new anti-tuberculosis agents from Hoffman-LaRoche,
isoniazid and iproniazid. Only the patients with poor prognosis
were initially treated; nevertheless, their condition improved dramatically.
In addition, Selikoff and Robitzek noted "a subtle general
stimulation... The patients exhibited renewed vigor and indeed this
occasionally served to introduce disciplinary problems."[5]
The promise of the cure for tuberculosis brought by the results
of the Sea View Hospital trials was also excitedly discussed in
the mainstream press. In 1952, learning of the stimulant-like side
effects of the isoniazid, the Cincinnati psychiatrist Max Lurie
decided to try it on his patients. In the following year, he and
Harry Salzer reported that isoniazid improved the depression in
two thirds of their patients and also coined the term antidepressant
to describe its action.[6] A similar story happened in Paris, where
Jean Delay, the head of psychiatry at Sainte-Anne Hospital, found
out from his pulmonology colleagues from Cochin Hospital about the
side effects of isoniazid. In 1952, that is even earlier than Lurie
and Salzer, Delay with the resident Jean-Francois Buisson also reported
the positive action of isoniazid on depressed patients.[7] For the
reasons unrelated to the efficacy, isoniazid as antidepressant was
soon overshadowed by more toxic iproniazid,[6] although it remains
one of the mainstays of the tuberculosis treatment. The mode of
antidepressant action of isoniazid is still unclear. It is speculated
that its effect is due to the inhibition of diamine oxidase coupled
with a weak inhibition of monoamine oxidase A.[8]

Another anti-tuberculosis drug tried at the same
time by Selikoff and Robitzek, iproniazid, was observed to have
a greater "psychostimulant" effect, albeit at the cost
of a greater toxicity.[9] Subsequently to the publications on isoniazid,
papers by Jackson Smith, Gordon Kamman, George Crane and Frank Ayd
describing the psychiatric applications of iproniazid also appeared,
and Ernst Zeller found iproniazid to be a potent monoamine oxidase
inhibitor.[10] Nevertheless, iproniazid had remained relatively
obscure until Nathan Kline, the influential and flamboyant head
of research at Rockland State Hospital, began its popularization
both in medical and popular press as a "psychic energizer".[11][10]
While isoniazid was not patentable,[6] Roche put a significant marketing
effort behind iproniazid, including promoting its off-label use
for depression.[10] Its sales grew massively in the following years,
until it was recalled from the market in 1961 due to the cases of
lethal hepatotoxicity.[10]

Imipramine

The discovery that a tricyclic ("three ringed")
compound had a significant antidepressant effect was also first
made in the early 1950s, by Roland Kuhn in a Swiss psychiatric hospital.
By that time antihistamine derivatives were coming in to use to
treat surgical shock and then as psychiatric neuroleptics. Although,
in 1955, reserpine was indicated to be more effective than placebo
in alleviating anxious depression, neuroleptics (literally "to
seize the neuron") were developing for use as sedatives and
antipsychotics.

In attempting to improve the effectiveness of
one of them, chlorpromazine, in conjunction with the Geigy pharmaceutical
company, Kuhn discovered that compound "G 22355" (manufactured
and patented in the US in 1951 by Häfliger and Schinder) had a beneficial
effect in patients with depression with mental and motor retardation.[12]
He first reported his findings on what he called a "thymoleptic"
(literally "taking hold of the emotions", by contrast
with neuroleptics, "taking hold of the nerves") in 1955/56
and they gradually became established, resulting in the marketing
of the first tricyclic antidepressant, imipramine, soon followed
by variants.

Later history

These new drug therapies became prescription-only
medications in the 1950s. It was estimated that no more than 50
to 100 people per million suffered from the kind of depression that
these new drugs would treat and pharmaceutical companies were not
enthusiastic. Sales through the 1960s remained poor compared to
the major tranquilizers (neuroleptics/antipsychotics) and minor
tranquilizers (such as benzodiazepines), which were being marketed
for different uses.

The term antidepressant is reported to have been coined by Lurie
and to not have been widely adopted until at least the 1960s.[13]
Imipramine remained in common use and numerous successors were introduced.
The field of MAO inhibitors remained quiet for many years until
"reversible" forms affecting only the MAO-A subtype were
introduced, avoiding some of the adverse effects.[14][15][16]

Most pharmacologists by the 1960s thought the main therapeutic
action of tricyclics was to inhibit norepinephrine reuptake, but
it was gradually observed that this action was associated with energizing
and motor stimulating effects whilst some antidepressant compounds
appeared to have differing effects through action on serotonin systems
(notably proposed by Carlsson and Lindqvist (1969) and Lapin and
Oxenkrug (1969)).

Researchers began a process of rational drug design to isolate
antihistamine-derived compounds that would 'selectively' (specifically)
target these systems. The first such compound to be patented, in
1971, was zimelidine, whilst the first released clinically was indalpine.
Fluoxetine (Prozac), FDA approved for commercial use in 1988, became
the first blockbuster SSRI. Fluoxetine was developed at Eli Lilly
in the early 1970s by Bryan Molloy, David Wong and others.[17][18]

While it had fallen out of favor in most countries through the
19th and 20th centuries, the herb St John's Wort had become increasingly
popular in Germany where Hypericum extracts eventually became licensed,
packaged and prescribed by doctors. Small-scale efficacy trials
were carried out from the 1970s and 1980s, and attention grew in
the 1990s following a meta-analysis of these.[19] It remained an
over-the-counter drug (OTC) or supplement in most countries and
research continued to investigate its neurotransmitter effects and
active components, particularly hyperforin[20][21]

SSRIs became known as "novel antidepressants"
along with other newer drugs such as SNRIs and NRIs with various
different selective effects, such as venlafaxine, duloxetine, nefazodone
and mirtazapine[22]

Types of Antidepressants

Selective serotonin reuptake inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs)
are a family of antidepressants considered to be the current standard
of drug treatment. It is thought that one cause of depression is
an inadequate amount of serotonin, a chemical used in the brain
to transmit signals between neurons. SSRIs are said to work by preventing
the reuptake of serotonin by the presynaptic nerve, thus maintaining
higher levels of 5-HT in the synapse. Recently, however, work by
two researchers has called into question the link between serotonin
deficiency and symptoms of depression, noting that the efficacy
of SSRIs as treatment does not in itself prove the link.[23] Recent
research indicates that these drugs may interact with transcription
factors known as "clock genes",[24] which may be important
for the addictive properties of drugs of abuse, and possibly in
obesity.[25][26]

Recent randomized controlled trials in Archives of General Psychiatry
showed that up to one-third of effects of SSRI Treatment can be
seen in first week. Early effects also shown to have secondary effect
of reducing absolute reduction in HDRS score by 50%. Even more recent
studies, published by the Archives of General Psychiatry note that
25% of so-called clinical depression does not meet a disease criteria
and should be considered to be ordinary sadness and adjustment to
the difficulties in life.

This family of drugs includes fluoxetine (Prozac),
paroxetine (Paxil), escitalopram (Lexapro, Esipram), citalopram
(Celexa), and sertraline (Zoloft). These antidepressants typically
have fewer adverse side effects than the tricyclics or the MAOIs,
although such effects as drowsiness, dry mouth, nervousness, anxiety,
insomnia, decreased appetite, and decreased ability to function
sexually may occur. Some side effects may decrease as a person adjusts
to the drug, but other side effects may be persistent. Though safer
than first generation antidepressants, SSRI's may not work as often,
suggesting the role of norepinephrine.

Serotonin-norepinephrine reuptake inhibitors
(SNRIs)

Serotonin-norepinephrine reuptake inhibitors (SNRIs)
such as venlafaxine (Effexor) and duloxetine (Cymbalta) are a newer
form of antidepressant that works on both norepinephrine and 5-HT.
They typically have similar side effects to the SSRIs, although
there may be a withdrawal syndrome on discontinuation that may necessitate
dosage tapering.

Noradrenergic and specific serotonergic antidepressants
(NASSAs)

Noradrenergic and specific serotonergic antidepressants
(NASSAs) form a newer class of antidepressants which purportedly
work to increase norepinephrine (noradrenaline) and serotonin neurotransmission
by blocking presynaptic alpha-2 adrenergic receptors while at the
same time minimizing serotonin related side-effects by blocking
certain serotonin receptors. The only example of this class in clinical
use is mirtazapine (Avanza, Zispin, Remeron).

Norepinephrine (noradrenaline) reuptake inhibitors
(NRIs)

Norepinephrine (noradrenaline) reuptake inhibitors
(NRIs) such as reboxetine (Edronax) act via norepinephrine (also
known as noradrenaline). NRIs are thought to have a positive effect
on concentration and motivation in particular, though they have
been known to increase aggression.

Norepinephrine-dopamine reuptake inhibitors

Tricyclic antidepressants (TCAs)

Tricyclic antidepressants are the oldest and include
such medications as amitriptyline and desipramine. Tricyclics block
the reuptake of certain neurotransmitters such as norepinephrine
(noradrenaline) and serotonin. They are used less commonly now due
to the development of more selective and safer drugs. Several side
effects include increased heart rate, drowsiness, dry mouth, constipation,
urinary retention, blurred vision, dizziness, confusion, and sexual
dysfunction. Toxicity occurs at approximately ten times normal dosages.
However, tricyclic antidepressants are still used because of their
high potency, especially in severe cases of clinical depression.

Monoamine oxidase inhibitor (MAOIs)

Monoamine oxidase inhibitors (MAOIs) such as phenelzine
(Nardil) may be used if other antidepressant medications are ineffective.
Because there are potentially fatal interactions between this class
of medication and certain foods (particularly those containing Tyramine),
as well as certain drugs, classic MAOIs are rarely prescribed anymore.
MAOIs work by blocking the enzyme monoamine oxidase which breaks
down the neurotransmitters dopamine, serotonin, and norepinephrine
(noradrenaline). MAOIs can be as effective as tricyclic antidepressants,
although they can have a higher incidence of dangerous side effects
(as a result of inhibition of cytochrome P450 in the liver). A new
generation of MAOIs has been introduced; moclobemide (Manerix),
known as a reversible inhibitor of monoamine oxidase A (RIMA), acts
in a more short-lived and selective manner and does not require
a special diet. Additionally, (selegiline) marketed as Emsam in
a transdermal form is not a classic MAOI in that at moderate dosages
it tends to effect MAO-B which does not require any dietary restrictions.

Augmenter drugs

Some antidepressants have been found to work more
effectively in some patients when used in combination with another
drug. Such "augmenter" drugs include tryptophan (Tryptan)
and buspirone (Buspar).

Tranquillizers and sedatives, typically the benzodiazepines, may
be prescribed to ease anxiety and promote sleep. Because of their
high potential for fostering dependence, these medications are intended
only for short-term or occasional use. Medications often are used
not for their primary function but to exploit what are normally
side effects. Quetiapine fumarate (Seroquel) is designed primarily
to treat schizophrenia and bipolar disorder, but a frequently reported
side-effect is somnolence. Therefore, this drug can be used in place
of an antianxiety agent such as clonazepam (Klonopin, Rivotril).

Antipsychotics
such as risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine
(Seroquel) are prescribed as mood stabilizers and are also effective
in treating anxiety. Their use as mood stabilizers is a recent phenomenon
and is controversial with some patients. Antipsychotics (typical
or atypical) may also be prescribed in an attempt to augment an
antidepressant, to make antidepressant blood concentration higher,
or to relieve psychotic or paranoid symptoms often accompanying
clinical depression. However, they may have serious side effects,
particularly at high dosages, which may include blurred vision,
muscle spasms, restlessness, tardive dyskinesia, and weight gain.

Antidepressants by their nature behave similarly to psychostimulants.
Antianxiety medications by their nature are depressants. Close medical
supervision is critical to proper treatment if a patient presents
with both illnesses because the medications tend to work against
each other.

Psycho-stimulants are sometimes added to an antidepressant regimen
if the patient suffers from anhedonia, hypersomnia and/or excessive
eating as well as low motivation. These symptoms which are common
in atypical depression can be quickly resolved with the addition
of low to moderate dosages of amphetamine or methylphenidate (brand
names Adderall and Ritalin, respectively) as these chemicals enhance
motivation and social behavior, as well as suppress appetite and
sleep. These chemicals are also known to restore sex drive. Extreme
caution must be used however with certain populations. Stimulants
are known to trigger manic episodes in people suffering from bipolar
disorder. They are also easily abused as they are effective substitutes
for Methamphetamine when used recreationally. Close supervision
of those with substance abuse disorders is urged. Emotionally labile
patients should avoid stimulants, as they exacerbate mood shifting.

Lithium remains the standard treatment for bipolar
disorder and is often used in conjunction with other medications,
depending on whether mania or depression is being treated. Lithium's
potential side effects include thirst, tremors, light-headedness,
and nausea or diarrhea. Some of the anticonvulsants, such as carbamazepine
(Tegretol), sodium valproate (Epilim), and lamotrigine (Lamictal),
are also used as mood stabilizers, particularly in bipolar disorder.

Prescription trends

In the United Kingdom the use of antidepressants
increased by 234% in the 10 years up to 2002.[28] In the United
States a 2005 independent report stated that 11% of women and 5%
of men in the non-institutionalized population (2002) now take antidepressants[29]
A 1998 survey found that 67% of patients diagnosed with depression
were prescribed an antidepressant.[30] A 2007 study purports that
25% of Americans were overdiagnosed with depression, regardless
of any medical intervention.[31] The findings were based on a national
survey of 8,098 people.

A 2002 survey found that about 3.5% of all people in France were
being prescribed antidepressants, compared to 1.7% in 1992, often
for conditions other than depression and often not in line with
authorizations or guidelines[32] Between 1996 and 2004 in British
Columbia, antidepressant use increased from 3.4% to 7.2% of the
population[33] Data from the Netherlands indicated an increasing
rate of prescriptions of SSRIs, and an increasing duration of treatment.[34]

Surveys indicate that antidepressant use, particularly of SSRIs,
has increased rapidly in most developed countries, driven by an
increased awareness of depression together with the availability
and commercial promotion of new antidepressants.[35] Antidepressants
are also increasingly used worldwide for non-depressive patients
as studies continue show the potential of immunomodulatory, analgesic
and anti-inflammatory properties in antidepressants.

The choice of particular antidepressant is reported to be based,
in the absence of research evidence of differences in efficacy,
on seeking to avoid certain side effects, and taking into account
comorbid (co-occurring) psychiatric disorders, specific clinical
symptoms and prior treatment history[36]

It is also reported that, despite equivocal evidence
of a significant difference in efficacy between older and newer
antidepressants, clinicians perceive the newer drugs, including
SSRIs and SNRIs, to be more effective than the older drugs (tricyclics
and MAOIs).[37] A survey in the UK found that male general physicians
were more likely to prescribe antidepressants than female doctors.[38]

Mechanisms of action

The therapeutic effects of antidepressants are
believed to be related to their effects on neurotransmitters. Monoamine
oxidase inhibitors (MAOIs) block the break-down of monoamine neurotransmitters
(serotonin and norepinephrine) by inhibiting the enzymes which oxidize
them, thus leaving higher levels still active in the brain (synaptic
cleft).

Tricyclic antidepressants (TCAs) prevent the reuptake of various
neurotransmitters, including serotonin, norepinephrine, and dopamine.
Selective serotonin reuptake inhibitors (SSRIs) more specifically
prevent the reuptake of serotonin (thereby increasing the level
of active serotonin in synapses of the brain). Other novel antidepressants
specifically affect serotonin and other neurotransmitters.

A theory centered on neurotransmitter effects appears to be incomplete,
however. Neurotransmitter levels are altered as soon as the antidepressant
chemicals build up in the bloodstream, but effects on mood appear
to occur several days or weeks later.

One explanation of this holds that the "down-regulation"
of neurotransmitter receptors—an apparent consequence of excess
signaling and a process that takes several weeks—is actually the
mechanism responsible for the alleviation of depressive symptoms.
Another hypothesis is that antidepressants may have some longer-term
effects due to the promotion of neurogenesis in the hippocampus,
an effect found in mice[40][41] Other animal research suggests that
antidepressants can also affect the expression of genes in brain
cells, by influencing "clock genes".[42]

New research suggests that delayed onset of clinical
effects from antidepressants indicates involvement of adaptive changes
in antidepressant effects. Rodent studies have consistently shown
upregulation of the 3, 5-cyclic adenosine monophosphate (cAMP) system
induced by different types of chronic but not acute antidepressant
treatment including serotonin and norepinephrine uptake inhibitors,
monoamine oxidase inhibitors, tricyclic antidepressants, lithium
and electroconvulsions. cAMP is synthesized from adenosine 5-triphosphate
(ATP) by adenylyl cyclase and metabolized by cyclic nucleotide phosphodiesterases
(PDEs).[43] Data also suggest antidepressants to have the ability
of modulating neural plasticity in longterm administration.[44]

Therapeutic efficacy

There is a large amount of research evaluating
the potential therapeutic effects of antidepressants, whether through
efficacy studies under experimental conditions (including randomized
clinical trials) or through studies of "real world" effectiveness.
A sufficient response to a drug is often defined as at least a 50%
reduction in self-reported or observed symptoms, with a partial
response often defined as at least a 25% reduction. The term remission
indicates a virtual elimination of depression symptoms, albeit with
the risk of a recurrence of symptoms or complete relapse. Full remission
or recovery signifies a full sustained return to a "normal"
psychological state with full functioning.

Clinical guidelines

The American Psychiatric Association 2000 Practice
Guideline for the Treatment of Patients with Major Depressive Disorder
[15] indicates that, if preferred by the patient, antidepressant
medications may be provided as an initial primary treatment for
mild major depressive disorder; antidepressant medications should
be provided for moderate to severe major depressive disorder unless
electroconvulsive therapy is planned; and a combination of antipsychotic
and antidepressant medications or electroconvulsive therapy should
be used for psychotic depression. It states that efficacy is generally
comparable between classes and within classes and that the initial
selection will largely be based on the anticipated side effects
for an individual patient, patient preference, quantity and quality
of clinical trial data regarding the medication, and its cost.

The UK National Institute for Clinical Excellence
(NICE) 2004 guidelines indicate that antidepressants should not
be used for the initial treatment of mild depression, because the
risk-benefit ratio is poor; that for moderate or severe depression
an SSRI is more likely to be tolerated than a tricyclic; and that
antidepressants for severe depression should be combined with a
psychological treatment such as Cognitive Behavioural Therapy. [16]

Long-term use

The therapeutic effects of antidepressants typically
do not continue once the course of medication ends, resulting in
a high rate of relapse. A recent meta-analysis of 31 placebo-controlled
antidepressant trials, mostly limited to studies covering a period
of one year, found that 18% of patients who had responded to an
antidepressant relapsed while still taking it, compared to 41% whose
antidepressant was switched for a placebo.[75] The American Psychiatric
Association guidelines advise four to five months of continuation
treatment on an antidepressant following the resolution of symptoms.
For patients with a history of depressive episodes, the British
Association for Psychopharmacology's 2000 Guidelines for Treating
Depressive Disorders with Antidepressants advise remaining on an
antidepressant for at least six months and as long as five years
or indefinitely.

Whether or not someone relapses after stopping
an antidepressant does not appear to be related to the duration
of prior treatment, however, and gradual loss of therapeutic benefit
during the course also occurs. A strategy involving the use of pharmacotherapy
in the treatment of the acute episode, followed by psychotherapy
in its residual phase, has been suggested by some studies.[76][77]

Medication failure

Approximately 30% of patients have remission of
depression with medications.[78] For patients with inadequate response,
either adding sustained-release bupropion (initially 200 mg per
day then increase by 100 mg up to total of 400 mg per day) or buspirone
(up to 60 mg per day) for augmentation as a second drug can cause
remission in approximately 30% of patients,[79] while switching
medications can achieve remission in about 25% of patients.[80]

Tolerance and dependence

Most antidepressants, including the SSRIs and
tricyclics, are known to produce tolerance (i.e. a decrease in the
effects of a drug over time), and withdrawal (particularly if abrupt)
may produce adverse effects, which can range from mild to extremely
severe.

Antidepressants do not seem to have all of the
same addictive qualities as other substances such as nicotine, caffeine,
cocaine, or other stimulants - in other words, while antidepressants
may cause dependence and withdrawal they do not seem to cause uncontrollable
urges to increase the dose due to euphoria or pleasure, and thus
do not meet the strict definition of an addictive substance. However,
antidepressants do meet the World Health Organisation definition
of "dependency-inducing", and indeed the SSRIs are listed
by the organisation as among the most strongly dependency-inducing
substances in existence.

If an SSRI medication is suddenly discontinued,
it may produce both somatic and psychological withdrawal symptoms,
a phenomenon known as "SSRI discontinuation syndrome"
(Tamam & Ozpoyraz, 2002). When the decision is made to stop
taking antidepressants it is common practice to "wean"
off of them by slowly decreasing the dose over a period of several
weeks or months, although often this will reduce the severity of
the discontinuation reaction, rather than prevent it. Most cases
of discontinuation syndrome last between one and four weeks, though
there are examples of patients (especially those who have used the
drugs for longer periods of time, or at a higher dose) experiencing
adverse effects such as impaired concentration, poor short-term
memory, elevated anxiety and sexual dysfunction, for months or even
years after discontinuation.

It is generally not a good idea to take antidepressants
without a prescription. The selection of an antidepressant and dosage
suitable for a certain case and a certain person is a lengthy and
complicated process, requiring the knowledge of a professional.
Certain antidepressants can initially make depression worse, can
induce anxiety, or can make a patient aggressive, dysphoric or acutely
suicidal. In certain cases, an antidepressant can induce a switch
from depression to mania or hypomania, can accelerate and shorten
a manic cycle (i.e. promote a rapid-cycling pattern), or can induce
the development of psychosis (or just the re-activation of latent
psychosis) in a patient with depression who was not psychotic before
the antidepressant.

Side effects

Antidepressants can often cause side effects,
and an inability to tolerate these is the most common cause of discontinuing
an otherwise working medication.

Side effects of SSRIs: Nausea, diarrhea, headaches. Sexual side
effects are also common with SSRIs, such as loss of libido, failure
to reach orgasm and erectile problems. Serotonin syndrome is also
a worrying condition associated with the use of SSRIs. The Food
and Drug Administration has included Black Box warnings on all SSRIs
stating how they double suicidality (from 2 in 1,000 to 4 in 1,000)
in children and adolescents who are prescribed these drugs.

Side effects of MAOIs (monoamine oxidase inhibitors):
Rare side effects of MAOIs like phenelzine (brand name: Nardil)
and tranylcypromine (brand name: Parnate) include liver inflammation,
heart attack, stroke, and seizures.Serotonin syndrome is a side
effect of MAOIs and SSRIs when they are combined.

Although recent drugs may have fewer side effects,
patients sometimes report severe side effects associated with their
discontinuation, particularly with paroxetine and venlafaxine. Additionally,
a certain percentage of patients do not respond to antidepressant
drugs. Another advantage of some newer antidepressants is they can
show effects within as few as five days, whereas most take four
to six weeks to show a change in mood. However, some studies show
that these medications might be even more likely to result in moderate
to severe sexual dysfunction. However, there are medications in
trials that appear to show an improved profile in regard to sexual
dysfunction and other key side effects.

MAO inhibitors can produce a potentially lethal hypertensive reaction
if taken with foods that contain high levels of tyramine, such as
mature cheese, cured meats or yeast extracts. Likewise, lethal reactions
to both prescription and over the counter medications have occurred.
Any patient currently undergoing therapy with an MAO inhibiting
medication should be monitored closely by the prescribing physician
and always consulted before taking an over the counter or prescribed
medication. Such patients should also inform emergency room personnel
and information should be kept with one's identification indicating
the fact that the holder is on MAO inhibiting medications. Some
doctors even suggest the use of a medical alert ID bracelet. Although
the reactions in question are dramatic when they happen, the total
number of deaths due to interactions and dietary concerns are comparable
to over-the-counter medications.

Antidepressants should be used with great care, usually in conjunction
with mood stabilisers, in the treatment of bipolar disorder, as
they can exacerbate symptoms of mania. They have also been known
to trigger mania or hypomania in some patients with bipolar disorder
and in a small percentage of patients with depression.[17] SSRIs
are the antidepressants most frequently associated with this side
effect.

In particular, it has been noted that the most dangerous period
for suicide in a patient with depression is immediately after treatment
has commenced, as antidepressants may reduce the symptoms of depression
such as psychomotor retardation or lack of motivation before mood
starts to improve. Although this appears to be a paradox, studies
indicate the suicidal ideation is a relatively common component
of the initial phases of antidepressant therapy, and it may be even
more prevalent in younger patients such as pre-adolescents and teenagers.
It is strongly recommended that other family members and loved ones
monitor the young patient's behavior, especially in the first eight
weeks of therapy, for any signs of suicidal ideation or behaviors.

Until the black box warnings on these drugs were issued by FDA
as well as by agencies in other nations, side effects and alerting
families to risk were largely ignored and downplayed by manufacturers
and practitioners. This may have resulted in some deaths by suicide
although direct proof for such a link is largely anecdotal. The
higher incidence of suicide ideation reported in a number of studies
has drawn attention and caution in how these drugs are used.

People under the age of 24 who suffer from depression are warned
that the use of antidepressants could increase the risk of suicidal
thoughts and behaviour. Federal health officials unveiled Proposed
changes to the labels on antidepressant drugs in December 2006 to
warn people of the inherent danger.

On September 6, 2007, the Centers for Disease
Control and Prevention reported suicide rate in American adolescents
(especially girls, 10 to 24 years old) increased 8% (2003 to 2004),
the largest jump in 15 years.[84] Specifically, in 2004 - 4,599
suicides in Americans ages 10 to 24, up from 4,232 in 2003, for
a rate of 7.32 per 100,000 people that age. Before, the rate dropped
to 6.78 per 100,000 in 2003 from 9.48 per 100,000 in 1990. The findings
also reinforced the fact that antidepressant drugs reduce suicide
risk. Psychiatrists found that the increase is due to the decline
in prescriptions of antidepressant drugs like Prozac to young people
since 2003, leaving more cases of serious depression untreated.
In a December 2006 study, The American Journal of Psychiatry said
that a decrease in antidepressant prescriptions to minors of just
a few percentage points coincided with a 14 percent increase in
suicides in the United States; in the Netherlands, the suicide rate
was 50% up, upon prescription drop.[85] The critics of this study
contend that the US "2004 suicide figures were compared simplistically
with the previous year, rather than examining the change in trends
over several years".[86] The pitfalls of such attempts to infer
a trend using just two data points (years 2003 and 2004) are further
demonstrated by the fact that, according to the new epidemiological
data, the suicide rate in 2005 in children and adolescents actually
declined despite the continuing decrease of SSRI prescriptions.
"It is risky to draw conclusions from limited ecologic analyses
of isolated year-to-year fluctuations in antidepressant prescriptions
and suicides. One promising epidemiological approach involves examining
the associations between trends in psychotropic medication use and
suicide over time across a large number of small geographic regions.
Until the results of more detailed analyses are known, prudence
dictates deferring judgment concerning the public health effects
of the FDA warnings."[87][88] Subsequest follow-up studies
have supported the hypothesis that antidepressant drugs reduce suicide
risk.[89] [90] However, the conclusion that societal suicide rate
decreases are due to antidepressant prescription is extraordinarily
dubious given the plethora of confounding variables.

Sexual dysfunction

Sexual dysfunction is a very common side effect,
especially with SSRIs. Common sexual side effects include problems
with libido (sexual desire), lack of interest in sex, and anorgasmia
(trouble achieving orgasm). [18] Although usually reversible, these
sexual side effects can, in rare cases, last for months or years
after the drug has been completely withdrawn. This disorder is known
as Post SSRI Sexual Dysfunction.

Bupropion, a dual reuptake inhibitor (NE and DA), in many cases
results in a moderately increased libido, due to increased dopamine
activity. This effect is also seen with dopamine reuptake inhibitors,
CNS stimulants and dopamine agonists, and is due to increases in
testosterone production (due to inhibition of prolactin) and increased
nitric oxide synthesis. Apomorphine, nefazodone and nitroglycerin
have been shown to reverse some sexual dysfunction via increased
nitric oxide activity. MAOIs are reported to have fewer negative
effects on sexual function and libido, particularly moclobemide
at a 1.9% rate of occurrence. Betanechol has been reported to reverse
MAOI-induced sexual dysfunction via its cholinergic agonist properties
(Gross 1982).

In order for the physician to select the appropriate
response, the patient should provide the physician with information
to distinguish between reduced libido (little or no desire for sex),
reduced sexual function (impotence, vaginal dryness) and anorgasmia,
as these have separate causes and prompt different treatment.

Thymoanesthesia

Closely related to sexual side effects is the
phenomenon of emotional blunting, or mood anesthesia. Many users
of SSRIs complain of apathy, lack of motivation, emotional numbness,
feelings of detachment, and indifference to surroundings. They may
describe this as a feeling of "not caring about anything anymore."
All SSRIs, SNRIs, and serotonergic TCAs are liable to cause this
effect to varying degrees, especially at higher dosages.

REM sleep

It is well recognized that virtually all major
antidepressant drugs but trimipramine suppress REM sleep and it
has, in fact, been proposed that the clinical efficacy of these
drugs largely derives from their suppressant effects on REM sleep.
The three major classes of antidepressant drugs, monoamine oxidase
inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective
serotonin reuptake inhibitors (SSRIs), profoundly suppress REM sleep.[19]
The MAOIs virtually completely abolish REM sleep, while the TCAs
and SSRIs have been shown to produce immediate (40-85%) and sustained
(30-50%) reductions in REM sleep. Abrupt discontinuation of MAOIs
can cause a temporary phenomenon known as "REM rebound"
in which the patient experiences extremely vivid dreams and nightmares.

Weight gain

Many antidepressants in all categories are associated
with weight gain usually in the range of 10-50 pounds but not uncommonly
upwards of 100 pounds. The specific cause is unknown, but it is
known that antidepressants are associated with increased cravings
(usually for high fat carbohydrates), an inability to feel full
despite ingestion of adequate calories, low energy levels and increased
daytime sleepiness which can lead to overeating and a lack of desire
to exercise, and dry mouth which can lead to ingestion of calorie-laden
beverages. Eating low fat, low protein carbohydrate snacks and carbohydrate-rich
dinners allows the brain to make serotonin which then controls appetite
and balances mood. Carbohydrates thus eaten, as part of a balanced
diet, by virtue of their effect on brain serotonin levels, thus
support weight loss in the setting of antidepressant weight gain.[91][92]

Controversy

Several studies have stimulated doubt about the
effectiveness of antidepressants. A 2002 study cited that the difference
between antidepressants and placebo is close to negligible.[93]

The paper in question has been severely criticized by independent
researchers, however. One reason for this is that it deals almost
exclusively with the SSRI class of medication. In leveling criticism
against the efficacy of SSRIs, critics state, it is not the best
paper, merely the most widely known one. Also, other classes of
antidepressants have demonstrated superior efficacy, and it has
been argued that this paper is "throwing the baby out with
the bathwater", while its thrust should in fact be leveled
at the serotonin hypothesis of depression.

Furthermore, not all patients necessarily respond to a given medication,
studies do not always address dosage versus drug-placebo differences
for those who do. Data submitted to the FDA can also underestimate
how a drug will perform in clinic practice, as studies sometimes
are designed as much for marketing purposes as they are to estimate
the magnitude of a medication's effects.[94]

Through a Freedom of Information Act request, two psychologists
obtained 47 studies used by the FDA for approval of the six antidepressants
prescribed most widely between 1987-99. Overall, antidepressant
pills worked 18% better than placebos, a statistically significant
difference, "but not meaningful for people in clinical settings",
says University of Connecticut psychologist Irving Kirsch. He and
co-author Thomas Moore released their findings in "Prevention
and Treatment", an e-journal of the American Psychological
Association.[20]

More than half of the 47 studies found that patients
on antidepressants improved no more than those on placebos, Kirsch
says. "They should have told the American public about this.
The drugs have been touted as much more effective than they are."
He says studies finding no benefit have been mentioned only on labeling
for Celexa, the most recently approved drug. The others included
in his evaluation: Prozac, Paxil, Zoloft, Effexor and Serzone.

Dr Joseph Glenmullen, a Harvard psychiatrist, has written a book
on the subject for the layperson; see link below.

In 2007, anti-depressants became the most prescribed
drug in the United States, causing more debate over the issue. Some
doctors believe this is a positive sign that people are finally
seeking help for their issues. Others disagree, saying that this
shows that people are becoming too dependent on anti-depressants.
[21]

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